Regulators of G protein signaling (RGS proteins) are critical modulators of signaling through the G protein coupled receptor (GPCR) family. GPCRs are the targets of a significant number of clinically used drugs including most drugs of abuse and RGS protein activity generally suppresses their function. Overexpression of RGS4 has been reported in rodent neuropathic pain models and abused drugs such as opioids and psychostimulants also affect RGS protein expression. Inhibition of RGS proteins can produce tissue-specific enhancement of GPCR agonist function with the potential to improve their specificity and reduce side-effects. The long term goals of this project are to discover small molecule chemical modulators of RGS protein activity - either to inhibit or enhance their function. This competitive revision (supplement) application takes off from our successful discovery of highly potent RGS4 inhibitors that have activity in vivo. This represents the first successful chemical targeting of RGS proteins. The specific aims of the present study are to: 1) establish whether the in vivo actions of the new RGS4 inhibitors are mediated through RGS4 by studies in RGS4 knockout mice, 2) determine whether our novel RGS4 inhibitors can enhance the analgesic actions of delta-opioid agonists which currently have limited efficacy. These studies would provide proof-of-principle for this novel approach to improving pharmacotherapy by chemically targeting RGS proteins. PUBLIC HEALTH RELEVANCE: Narcotic analgesics, including morphine and heroin, are major drugs of abuse. They are important for control of pain and their actions are modulated inside the cell by a newly discovered mechanism. We have just developed inhibitors of that mechanism that could provide improved pain relief with a unique class of opiate drugs that may have decreased abuse potential.